Co-dependence on ethanol and nicotine is the most common of polydrug addictions. Previous studies have suggested that sensitivity of these two drugs on certain measures are genetically correlated; those animals which are more sensitive to one agent are also more sensitive to the other. This correlation may have arisen because ethanol acts at specific nicotinic receptor subtypes to modulate their function. Preliminary evidence supports this. The overall hypothesis of this research is that ethanol acts at nicotinic cholinergic receptors and that this interaction is the basis for the observed genetic correlation in sensitivities between ethanol and nicotine and the common co-use of these agents. The long term goal of this research is to determine the specific mechanism(s) by which ethanol and nicotine interact to produce co-dependence. We will work toward this goal by confirming that nicotine and ethanol sensitivities are genetically correlated. Potential mechanisms for interactions between ethanol and nicotine will be examined and characterized by focusing on the effects of ethanol and interactions with nicotine on nicotine acetylcholine receptors (nAChRs). Previous studies suggest highly that ethanol and nicotine sensitivities are genetically correlated. Studies are proposed to replicate, confirm and expand on our preliminary studies with the HAS/CAS/LAS selectively bred rat lines. Because studies in inbred strains of mouse have demonstrated that numbers of nicotinic binding sites are correlated with nicotine sensitivity, the numbers of binding sites for [3H]nicotine and alpha-[125]bungarotoxin will be measured in these animals. Pharmacokinetic analyses with nicotine will also be conducted. Evidence suggests that ethanol may act at nAChRs. We will use a Xenopus oocyte expression/recording system to screen specific nAChR subtypes for responsiveness to ethanol. By conducting dose-response and time course analyses we will be able to determine at which receptor subtypes ethanol acts (efficacy studies) and to assess the degree to which these subtypes are sensitive (potency studies). Additionally, we will be able to assess the nature of ethanol's actions at a particular subtype. We hypotheize that ethanol will modulate the responsiveness of nAChR subtypes to agonists in a subtype- and concentration-dependent fashion. Specifically, we hypothesize that the actions of ethanol will include both attenuation and enhancement of nicotinic responses.